Infantile Alexander Disease: A GFAP Mutation in Monozygotic Twins and Novel Mutations in Two Other Patients

M. Meins; K. Brockmann; S. Yadav; M. Haupt; J. Sperner; U. Stephani; F. Hanefeld

doi:10.1055/s-2002-34495

Neuropediatrics, Table of Contents

Neuropediatrics 2002; 33(4): 194-198
DOI: 10.1055/s-2002-34495

Original Article

Georg Thieme Verlag Stuttgart · New York

Infantile Alexander Disease: A GFAP Mutation in Monozygotic Twins and Novel Mutations in Two Other Patients[*]

M. Meins¹ , K. Brockmann² , S. Yadav¹ , M. Haupt³ , J. Sperner⁴ , U. Stephani⁵ , F. Hanefeld²

¹ Department of Human Genetics, University of Göttingen, Germany
² Department of Neuropaediatrics, University Children's Hospital, Göttingen, Germany
³ Children's Hospital, Erfurt, Germany
⁴ Department of Paediatrics, Medical University of Lübeck, Germany
⁵ Neuropaediatric Department, University Children's Hospital, Kiel, Germany

Abstract

Alexander disease (AD) is a rare disorder of cerebral white matter due to a dysfunction of astrocytes. The most common infantile form presents as a megalencephalic leukodystrophy. Recently, heterozygous de novo mutations in the glial fibrillary acidic protein gene (GFAP) have been demonstrated to be associated with AD. We report heterozygous mutations in GFAP in 5 patients, including a pair of monozygotic twins, with clinical and neuroradiological features of infantile AD. Novel mutations were detected affecting nucleotides 304 T → C (L97 P) and 730 G → C (R239 P) in two other patients. None of the parents of our patients carried the mutations stressing dominant de novo mutations as the cause of AD. The presence of an identical mutation 250 G → A (R79 H) in both monozygotic twins with infantile AD points to the origin of these GFAP mutations in germ cells or very early postzygotic stages.

Key words

GFAP Gene - Glial Fibrillary Acidic Protein - Alexander Disease - Leukodystrophy

Full Text

References

1 Alexander W S. Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain. 1949; 72 373-381
2 Borrett D, Becker L E. Alexander's disease. A disease of astrocytes. Brain. 1985; 108 367-385
3 Brenner M, Johnson A B, Boespflug-Tanguy O, Rodriguez D, Goldman J E, Messing A. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet. 2001; 27 117-120
4 Cole G, De Villiers F, Proctor N S, Freiman I, Bill P. Alexander's disease: case report including histopathological and electron microscopic features. J Neurol Neurosurg Psychiatry. 1979; 42 619-624
5 Friede R L. Alexander's Disease. Arch Neurol. 1964; 11 414-422
6 Head M W, Corbin E, Goldman J E. Overexpression and abnormal modification of the stress proteins alpha B-crystallin and HSP27 in Alexander disease. Am J Pathol. 1993; 143 1743-1753
7 Herndon R M, Rubinstein L J, Freeman J M, Mathieson G. Light and electron microscopic observations on Rosenthal fibers in Alexander's disease and in multiple sclerosis. J Neuropathol Exp Neurol. 1970; 29 524-551
8 Iwaki T, Kume-Iwaki A, Liem R K, Goldman J E. Alpha B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain. Cell. 1989; 57 71-78
9 King R D, Sternberg M J. Identification and application of the concepts important for accurate and reliable protein secondary structure prediction. Protein Sci. 1996; 5 2298-2310
10 Leegwater P A, Yuan B Q, van der Steen J, Mulders J, Konst A A, Boor P K. et al . Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 2001; 68 831-838
11 Messing A, Head M W, Galles K, Galbreath E J, Goldman J E, Brenner M. Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol. 1998; 152 391-398
12 Messing A, Goldman J E, Johnson A B, Brenner M. Alexander disease: New insights from genetics. J Neuropathol Exp Neurol. 2001; 60 563-573
13 Pridmore C L, Baraitser M, Harding B, Boyd S G, Kendall B, Brett E M. Alexander's disease: Clues to diagnosis. J Child Neurol. 1993; 8 134-144
14 Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M, N'Guyen S. et al . Infantile Alexander disease: Spectrum of GFAP mutations and genotype-phenotype correlation. Am J Hum Genet. 2001; 69 1134-1140
15 Russo L S, Aron A, Anderson P J. Alexander's disease: A report and reappraisal. Neurology. 1976; 26 607-614
16 Schwankhaus J D, Parisi J E, Gulledge W R, Chin L, Currier R D. Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia. Neurology. 1995; 45 2266-2271
17 Springer S, Erlewein R, Naegele T, Becker I, Auer D, Grodd W. et al . Alexander disease - classification revisited and isolation of a neonatal form. Neuropediatrics. 2000; 31 86-92
18 van der Knaap M S, Barth P G, Stroink H, van Nieuwenhuizen O, Arts W F, Hoogenraad F. et al . Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol. 1995; 37 324-334
19 van der Knaap M S, Naidu S, Breiter S N, Blaser S, Stroink H, Springer S. et al . Alexander disease: Diagnosis with MR imaging. AJNR Am J Neuroradiol. 2001; 22 541-552

1 M. M. and K. B. contributed equally to this work

Dr. Moritz Meins

Institute of Human Genetics, University of Göttingen

Heinrich-Düker-Weg 12

37073 Göttingen

Germany

Email: mmeins@gwdg.de